Iron Reduction Therapy in Ex-Thalassemics - Long Term Outcome

Introduction: After successful allogeneic hematopoetic stem cell transplantation (aHSCT) for thalassemia major (TM), these "ex-thalassemics" require effective management of pre-existing transfusion related complications. Reduction of iron overload which is prevalent in almost all of these patients is one of the major goals of this therapy. Even though several thousand aHSCTs have been done for TM, there is very limited data on the approach to iron reduction therapy (IRT) and its outcome. We report the outcome of IRT in the largest cohort of ex-thalassemics to be reported so far.

Patients & Methods: Patients with TM who had aHSCT between January 2001 and December 2012, and who had IRT (phlebotomy and / or iron chelation - deferoxamine / deferasirox) with at least 3 years follow-up were included in this analysis. The major determinants for initiation of IRT were a stable graft and no other ongoing long term complications such as graft vs host disease or infections. The type of IRT advised depended on the baseline haemoglobin (>10.5g/dl), ease of venous access, level of serum ferritin as well patient / family preferences. Reduction in serum ferritin level was calculated as a function of time.

Results: Out of 281 aHSCT for TM during this period, 213 (75.8%) were successful. 149(70.0%) of these could be included in this analysis as per the criteria mentioned above. The median age was 7 years (range:1-18) and 92(61.7%) belonged to Pesaro class 3. Median ferritin at aHSCT was 2480ng/ml (range:866-8921). IRT was reinitiated at a median of 15 months (range:5-53) post aHSCT. 10 patients (6.8%) with a median serum ferritin at aHSCT of 2010ng/ml (range:1216-2830)were treated with phlebotomy alone, while 61(40.9%) with a median serum ferritin at aHSCTof 2161ng/ml (range:1341-7660) received chelation alone and 78 (52.3%) with a median serum ferritin at aHSCT of 2806ng/ml (range:866-8921) were treated with the combination. Reduction in serum ferritin/month [absolute quantity (ng/ml/month)was significantly higher in those who received combination therapy: 87(range:33-195), 129 (range:17-1011) and 147 (range:27-1427) in the phlebotomy, chelation and combination therapy groups, respectively (p=0.031).With a median follow up of 80 months (range:37-182), target ferritin level of less than 300ng/ml was achieved in 59 patients (40%), in a median duration of 41 months (range:3-136) and less than 500ng/ml was achieved in 88 patients (59%) in a median duration of 41 months (range:3-136). (Fig 1a) No significant toxicities related to IRT were noted in this cohort. Comparison of the characteristics of patients who achieved the target ferritin of <500ng/ml] versus those with ongoing IRT [ferritin >500ng/ml) are shown in the table. Patients in class III risk category and starting serum ferritin levels >2500 ng/ml had delayed responses to IRT and required much longer to reach target levels. (Fig 1b) Delay in initiation of IRT, intensity of the protocol and compliance with IRT also affected outcome.

Conclusion: Our data shows that IRT ex-thalassemics needs careful attention as soon as possible after aHSCT with the goal of rapid reduction to target levels. A combination of phlebotomy and iron chelators work faster in reducing iron overload. More data is needed to develop the optimal protocols for IRT in ex-thalassemics.

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